PROJECT SUMMARY/ABSTRACT The ECOG-ACRIN Thoracic Integrated Translational Research Center (EA-ITSC) comprises a team of accomplished researchers with a proven track record of collaborative work to improve outcomes for patients with lung cancer. The EA-ITSC, funded in 2014 by the NCI (U10) at the same time as the formation of the National Clinical Trials Network (NCTN), has played a major role in developing novel approaches for risk stratification, molecular testing, and treatment of lung cancer. This group has also been responsible for guiding the development of biomarker-driven clinical trials initiated by the ECOG-ACRIN Thoracic Malignancies Committee. Our highly collaborative team approach includes sharing specimens across institutions, conducting pilot projects that are of direct relevance to NCTN trials and guiding the translational research components of all newly developed ECOG-ACRIN thoracic malignancies trials. Our overarching goal is to develop novel biomarkers to enhance the efficacy of immunotherapy, overcome resistance to targeted agents and to identify combination treatment approaches to enhance the efficacy of existing therapies in lung cancer within the context of the NCTN. With this application, we propose to continue our research work with direct relevance to the NCTN, with the following specific aims: 1) To develop genomic, epigenomic, and proteomics approaches to enhance biomarker discovery efforts in ongoing and planned ECOG-ACRIN studies; 2) To conduct pilot studies on existing ECOG- ACRIN and institutional lung cancer tumor specimens that will lead to prospective NCTN clinical trials; and 3) To guide the development of translational research components of ECOG-ACRIN Thoracic trials and promote collaborations with lung cancer SPORE and P01 institutions. The EA-ITSC will have a robust pilot projects program from years 2-6 of this award that will invite participation from all the NCTN network groups, institutions with lung cancer SPORE and P01 awards, to bring the best science to NCTN clinical trials.